Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Abstract

The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Keywords: DNA damage response; MTH1; MTHFD2; SAMHD1; cancer; dNTP metabolism.

Fig. 1

Mechanism of action of clinical MTH1 inhibitors. Schematic detailing the current model for the mechanism of action of MTH1 inhibitors under clinical investigation. TH1579 (karonudib, OXC‐101) and related compound TH588 are dual inhibitors of the catalytic activity of MTH1 and microtubule polymerisation. These compounds arrest cells in mitosis leading to the accumulation of reactive oxygen species (ROS) that subsequently oxidise the purine triphosphate pool. The dNTPase activity of MTH1 is important during this arrest to prevent the use of these modified nucleotides in mitotic DNA synthesis, which is cytotoxic to cancer cells by a yet to be determined mechanism. Figure adapted from [41] and [59], and created in BioRender. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 2

Mechanism of action of MTHFD2 inhibitors. Schematic detailing the proposed mechanism for antitumour effect of MTHFD2 inhibition. MTHFD2 supports de novo thymidylate (dTMP) synthesis by providing methyl‐tetrahydrofolate (CH₂‐THF), and thus, loss of MTHFD2 activity depletes dTTP pools, leading to thymineless‐induced replication stress. In parallel, loss of dTMP production results in the accumulation of dUMP, the substrate of thymidylate synthase (TYMS), which is subsequently phosphorylated to its triphosphate form dUTP. Excess dUTP is incorporated into DNA leading to elevated genomic uracil exacerbating replication stress, ultimately resulting in DNA strand breaks and cell death. Figure created in BioRender. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 3

Strategies to target the drug resistance factor SAMHD1. SAMHD1 is a dNTP hydrolase that removes the triphosphate moiety from several anticancer nucleoside triphosphate analogues, thus converting the active metabolites of these therapies back to their inactive prodrug form. Current strategies to target SAMHD1 include proteasomal degradation, which can be achieved by delivery of the viral protein‐X (Vpx) into cancer cells. Direct catalytic inhibitors of SAMHD1 (SAMHD1i), which although have been documented against recombinant SAMHD1 in vitro, are yet to be shown to work in cell models. Indirect pharmacological approaches such as inhibitors of ribonucleotide reductase (RNRi) can suppress the drug resistance activity of SAMHD1 in cancer cells by perturbing nucleotide metabolism. Figure created in BioRender. [Colour figure can be viewed at wileyonlinelibrary.com]